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Genetic variants (SNPs) Interpretation Guide

caledonia

Senior Member
Hi All,

As there are more and more people coming on the forum asking for help with their SNPs, it's starting to get overwhelming. Therefore, I've prepared this guide to help people interpret their SNPs.

I'm asking for everyone's help to please bookmark this page and then refer people to this guide when they ask for help with their SNPs.

I will also put a link to this guide in my signature links, so you can also access it through any of my thousands of posts.

Caledonia
 

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Critterina

Senior Member
Messages
1,238
Location
Arizona, USA
Caledonia,

This is a major work that you've done here. Of course, like always, there's stuff you say that I have difficulty with. Could you help me out with these two paragraphs?

SHMT (SHMT1 C1420T) is part of the folate cycle (where MTHFR is). An SHMT mutation often shifts the methylation cycle away from both the long and short routes through the methylation cycle into a side reaction, which is not productive for methylation...

To support SHMT, take a low dose of folinic acid to help shift methylation activity back to the short and long routes around the cycle. Yasko also suggests using lactoferrin (which helps to control iron levels to regulate SHMT). Heartfixer also suggests methylfolate.

Would you give me a reference to the side reaction? And what the long and short routes are? Here are three things I need to understand better. Maybe I was under a mistaken impression about alternative routes somewhere along the line, since I have the SHMT +/+ and have normal amounts of serine and glycine.

Folinic acid (5,10-methylene THF) as a supplement for people with SHMT and MTHFR A1298C just seems wrong to me. It essentially shuts down the conversion of MTHF to folinic acid, by deactivating BH4, so that neurotransmitter production happens much less, lowering serotonin and dopamine, exacerbating depression and anxiety, and maybe the other things that are associated with A1298C. For me, folinic acid didn't make me feel worse, but it did induce something close to narcolepsy. Please explain why you'd make this suggestion.

I have other issues with calling A1298C a minor mutation (bipolar disorder and autism don't seem like minor consequences to me) and the MTR/MTRR explanation. But let's just take one SNP at a time, and for now, it's SHMT. I think we will all get to a better understanding through this discussion.

Respectfully,
Critterina
 

caledonia

Senior Member
Would you give me a reference to the side reaction?

I purposely left this a little vague because I didn't want to junk it up with too much technical stuff. But anyway, it's thymidine.
Source: http://www.dramyyasko.com/resources/autism-pathways-to-recovery/chapter-6/

Understanding SHMT Mutations
Based on the research of Dr. Patrick Stover, I’ve concluded that the SHMT mutation often shifts the methylation cycle away from both the long and short routes through the methylation cycle into a side reaction that leads to the production of thymidine (see illustration.)

Supplementing with nucleotides, which are a form of our DNA bases, can help to both support thymidine, while maintaining appropriate methylation cycle activity. In addition, both iron and a form of folate called “5 formyl THF ” help to regulate SHMT activity. That’s why using lactoferrin (which helps to control iron levels) along with low doses of 5 formyl THF (found in the product, ActiFolate) help shift methylation activity back to the short and long routes around the cycle.

And what the long and short routes are?

It helps if you can look at a methylation cycle diagram, which is represented as a circle. The long route starts about 9 o'clock on the left with MTR, going around clockwise making methionine, then methyl groups, then homocysteine. Then at the bottom, (6 o'clock) there's a three way split between going up the BHMT pathway, going down the CBS pathway, or continuing back around the circle to MTR.

The short route is up the BHMT pathway to make methionine, then around to the right to make methyl groups, and methionine, then back down to the three way split and up the BHMT pathway again.

Folinic acid (5,10-methylene THF) as a supplement for people with SHMT and MTHFR A1298C just seems wrong to me. It essentially shuts down the conversion of MTHF to folinic acid, by deactivating BH4, so that neurotransmitter production happens much less, lowering serotonin and dopamine, exacerbating depression and anxiety, and maybe the other things that are associated with A1298C. For me, folinic acid didn't make me feel worse, but it did induce something close to narcolepsy. Please explain why you'd make this suggestion.

These aren't my suggestions, just based on the research, which I've listed. Functionally, some people get along with folinic and some don't. So you basically have to trial it, and see if it works for you (or not). There may some other genes interfering, which we haven't figured out yet. If you don't have SHMT working properly, you'll have a decreased capacity to make DNA and RNA bases, which then can't eventually be methylated to make DNA and RNA, so that's not good either.

Iron and nucleotides are two other possibilities for supplementation.

I have other issues with calling A1298C a minor mutation (bipolar disorder and autism don't seem like minor consequences to me) and the MTR/MTRR explanation. But let's just take one SNP at a time, and for now, it's SHMT. I think we will all get to a better understanding through this discussion.

It's "minor" in respect to the amount of methylfolate it reduces, but of course, not minor in it's effects on BH4 and thus neurotransmitters, mental health, addiction and so forth.
 

Critterina

Senior Member
Messages
1,238
Location
Arizona, USA
@caledonia ,

Thanks. I'll have to take another look. I'm familiar with the BHMT and the MTR pathways, I just didn't think of them as long and short, although if you draw them the way you describe, the diameter is a shorter route than half the circumference of the circle, so with that image in mind, it makes sense.

I haven't always agreed with Dr. Yasko's interpretation of other people's research (e.g. CBS C699T), and I don't take heartfixer as a primary source either, since AMRI makes a lot of the same "mistakes" (in my opinion) that Yasko does. (Not to discredit either of them for the great work they do, not in the least - this is about what you can and can't tell from the research ONLY.) So it looks like I'll have to go read Dr. Stover's work myself.

You said "These aren't my suggestions, just based on the research, which I've listed." For me, there is a world of difference between research and suggestions. I think that's where you and I probably have our biggest philosophical differences. And that's OK. Seeing how you interpret SNPs, it made me think about how I interpret SNPs, and if I were going to write something like you did, how would I explain it. It would be an interesting exercise, but don't hold your breath for it.

I actually tried Holistic Health's SHMT+ spray. No noticeable difference, but I was already on methylation supplements. Whoops, thunder here - need to unplug the computer!
 

caledonia

Senior Member
@caledonia ,

Thanks. I'll have to take another look. I'm familiar with the BHMT and the MTR pathways, I just didn't think of them as long and short, although if you draw them the way you describe, the diameter is a shorter route than half the circumference of the circle, so with that image in mind, it makes sense.

I haven't always agreed with Dr. Yasko's interpretation of other people's research (e.g. CBS C699T), and I don't take heartfixer as a primary source either, since AMRI makes a lot of the same "mistakes" (in my opinion) that Yasko does. (Not to discredit either of them for the great work they do, not in the least - this is about what you can and can't tell from the research ONLY.) So it looks like I'll have to go read Dr. Stover's work myself.

You said "These aren't my suggestions, just based on the research, which I've listed." For me, there is a world of difference between research and suggestions. I think that's where you and I probably have our biggest philosophical differences. And that's OK. Seeing how you interpret SNPs, it made me think about how I interpret SNPs, and if I were going to write something like you did, how would I explain it. It would be an interesting exercise, but don't hold your breath for it.

I actually tried Holistic Health's SHMT+ spray. No noticeable difference, but I was already on methylation supplements. Whoops, thunder here - need to unplug the computer!

Well, I guess technically, it's a compilation of other's interpretations of the research, along with their clinical observations.

There was just a need to pull this all together into one place, in an easy to read manner. Trying to read through Yasko, Heartfixer, Rich Vank, Ben Lynch, etc. can be daunting for a newbie, especially one with brain fog.

I encourage people to do further research and learn as much as they can about this stuff. Then share it with others, so we can all learn, and hopefully figure out how to make ourselves better.
 

ahmo

Senior Member
Messages
4,805
Location
Northcoast NSW, Australia
@Critterina
Folinic acid (5,10-methylene THF) as a supplement for people with SHMT and MTHFR A1298C just seems wrong to me. It essentially shuts down the conversion of MTHF to folinic acid, by deactivating BH4, so that neurotransmitter production happens much less, lowering serotonin and dopamine, exacerbating depression and anxiety, and maybe the other things that are associated with A1298C. For me, folinic acid didn't make me feel worse, but it did induce something close to narcolepsy. Please explain why you'd make this suggestion.

So what's your position on folinic acid? I'm glad you've picked up on it, I'm just so impressed w/ the guide, haven't reviewed it forensically. (I'm pretty much incapable of reviewing anything forensically!:lol:)

I ask because I found folinic did nothing for me, tho I tried it several times. I eventually found that vegetable folate, ie. folinic, in fact blocks Mfolate for me. I had to eliminate my green veg to bring down my Mfolate dose from 25mg to 15mg.

@caledonia Thanks for this wonderful compilation. I'll not only refer folks to it, but also to this conversation.:thumbsup:
 

caledonia

Senior Member
@Critterina

So what's your position on folinic acid? I'm glad you've picked up on it, I'm just so impressed w/ the guide, haven't reviewed it forensically. (I'm pretty much incapable of reviewing anything forensically!:lol:)

I ask because I found folinic did nothing for me, tho I tried it several times. I eventually found that vegetable folate, ie. folinic, in fact blocks Mfolate for me. I had to eliminate my green veg to bring down my Mfolate dose from 25mg to 15mg.

@caledonia Thanks for this wonderful compilation. I'll not only refer folks to it, but also to this conversation.:thumbsup:

Based on our experiences here on the forum, folinic is tolerated by some people, but not others. So if it's working for you, take it. If not, avoid it. As the reason for this is unknown*, the only way to know is to cautiously trial it and observe how your body reacts.

*I just reread that whole long thread on the MTHFS gene possibly causing this, but we weren't able to come to any definite conclusion.

Alternatives for support are iron and nucleotides.
 

Critterina

Senior Member
Messages
1,238
Location
Arizona, USA
@caledonia ,

I think I participated in that whole MTHFS thing, and I was the only homozygous mutant in the one SNP we had as the most likely candidate. And at the time, I was trying to decide whether I could tolerate it or not, since by manipulating other supplements, I lost the narcolepsy...I was thinking that was an SHMT discussion, but now I am thinking MTHFS. I really need to transfer my files onto this computer, so I can look things up.

@ahmo ,

My position on folinic acid comes from the place it is in the folate cycle and the effects of the MTHFR C677T and A1298C SNPs. Folinic acid is the last step before methylfolate. The MTHFR enzyme facilitates the reaction, which can go both ways. So people with C677T are inefficient at converting folinic acid to methylfolate - that's the big deal about that SNP - and it does little good for them to take it.

And people with A1298C are inefficient at converting methylfolate back to folinic acid. It didn't seem like that would be important, since they can convert it to methylfolate, and since they are taking the folinic, they will have plenty of that, too. In fact, that was my reasoning that led me to trial it. Here's the rub: The problems associated with A1298C stem from a lack of BH4, which is used for a lot of things, but in particular it makes serotonin and dopamine. The important part is not how much you have, but which way the cycle turns.

BH4 and BH2 are the two forms of biopterin in the biopterin cycle. BH4 turns into BH2 when it makes serotonin and dopamine, when it converts folinic acid to methylfolate, and other things that are important. To recycle it back to BH4 takes one of two enzymes. The first is MTHFR, in the reaction that converts methylfolate to folinic acid. If you're taking folinic acid, the MTHFR enzyme is going to be converting it to methylfolate, not the other way round, not the way you want it to be turning. It's trying to achieve equilibrium and you're pushing the reaction one way, when to make BH4, it needs to go the other.

(The other enzyme is IDHPR. I don't know much about it, whether there are SNPs that affect it's efficiency or not. I assume so, which probably contributes to why some people suffer more from their A1298C SNP than others. Anyway, we're not doing anything about that, so it is what it is.)

So, my "logical" reason to think that the only people who should really be taking folinic acid are those with neither of the above MTHFR SNP, is based on this explanations. I can't dispute that I certainly don't have the whole story, and caledonia's "cautiously trial" recommendation is based on the experience of many people - probably both healthcare practitioners (who may not have access to the patient SNPs) and people writing in this forum (who have a variable level of experience). I don't mean to discount it. I just probably wouldn't recommend folinic to treat these SNPs.
 

ahmo

Senior Member
Messages
4,805
Location
Northcoast NSW, Australia
@Critterina I wrote of my experiences in the High Methylfolate thread at the time. I had to search out this veg folinic problem because it became evident that there was a big burden on my adrenals. The nearest info I could find suggested that adrenals need folate, so I reasoned that they were folate-sensitive, and maybe this was why I was having adrenal symptoms.

As I was already engaged in an intensive detox protocol, I unwittingly opened the process full throtle by eliminating my cooked veg. At the time I thought the cooked veg was acting as a brake on my veg juice and the rest of my procedure. In retrospect it's pretty clear that removing the veg folinic unblocked methylation in a big way! I needed to stop all Mfolate for days to get things back under control.

Yes, even now at 15mg, my Mfolate tab is expensive. I'm using about 6 leaves Romaine lettuce w/ a good size carrot as juice, w/ the carrot remains in my broth. that's it for my veg intake, sadly:meh:
 

Peyt

Senior Member
Messages
678
Location
Southern California
First of all I wanted to say thank you so much for compiling this info. and posting it.
I have ACAT +/- which is the first thing to take care of on the list.
looking at this supplement from Yasko: ACAT / BHMT - Fatty Acid Digestion - Energy Conversion - Holistic Health
But honestly it's so expensive!!!! When I look at the ingredients, 60% of those ingredients I take already (Besides Ox Bile which I hate because it gives me bad breath) .... It's nice to see that I can now correlate my problems of
fat mal-digestion to ACAT but need a cheaper supplement to help me with.... Since I still have my gallbladder, my Chinese herbalist use to tell me if I eat some green leafy veggies with every meal, it will help the gallbladder contract and thus pour some bile into the intestines..... I also notice when I take HCL with my meals I digest fats
better. But HCL gives me some side effects like I get easily agitated and angered, and I wonder if I have a problem with Betaine (which I think HCL is)...but if I can figure out a way around HCL's side effect, I rather just take some HCL and green leafy veggies than buy this supplement. Any suggestions would be appreciated. Thanks

Also, as you may know HCL helps with low stomach acid, and the fact that it helps me with digestion so much also raises the question : Do I have H.Pylori? H. Pylori reduces stomach acid which will then result in gallbladder not producing and injecting enough bile into the intestines (it is gallbladder's job to bring the food that leaves the stomach which has a high acidic ph to a more neutral alkaline by contracting and injecting bile) ... Anyways, I took some antibiotics for H.Pylori about 10 years ago and since then conventional medicine lab work has not shown that I have H.Pylori, but not sure how good those blood tests are.
Anyways, your thoughts and comments are appreciated.
Peyt
 

Gingergrrl

Senior Member
Messages
16,171
@caledonia Thank you for creating the SNP Guide and I am in the process of printing it out now. How much I will understand is another story :D.
 

Peyt

Senior Member
Messages
678
Location
Southern California
Hello again, since I put up my last post I have learned that Betaine is a methyl donor... that explains why it helped with stomach acid and fat digestion but caused agitation and anger in my case... I am Comt +/+ on both Comt genes and therefore an over-methylator with excess dopamine and norepinephrine... so now my question is, is there anyway to increase the stomach acid without having to use a methyl donor? oddly enough, I have tried lemon juice which works but causes the same side effects for me .... I guess I am stuck at step 1!
 

caledonia

Senior Member
First of all I wanted to say thank you so much for compiling this info. and posting it.
I have ACAT +/- which is the first thing to take care of on the list.
looking at this supplement from Yasko: ACAT / BHMT - Fatty Acid Digestion - Energy Conversion - Holistic Health
But honestly it's so expensive!!!! When I look at the ingredients, 60% of those ingredients I take already (Besides Ox Bile which I hate because it gives me bad breath) .... It's nice to see that I can now correlate my problems of
fat mal-digestion to ACAT but need a cheaper supplement to help me with.... Since I still have my gallbladder, my Chinese herbalist use to tell me if I eat some green leafy veggies with every meal, it will help the gallbladder contract and thus pour some bile into the intestines..... I also notice when I take HCL with my meals I digest fats
better. But HCL gives me some side effects like I get easily agitated and angered, and I wonder if I have a problem with Betaine (which I think HCL is)...but if I can figure out a way around HCL's side effect, I rather just take some HCL and green leafy veggies than buy this supplement. Any suggestions would be appreciated. Thanks

Also, as you may know HCL helps with low stomach acid, and the fact that it helps me with digestion so much also raises the question : Do I have H.Pylori? H. Pylori reduces stomach acid which will then result in gallbladder not producing and injecting enough bile into the intestines (it is gallbladder's job to bring the food that leaves the stomach which has a high acidic ph to a more neutral alkaline by contracting and injecting bile) ... Anyways, I took some antibiotics for H.Pylori about 10 years ago and since then conventional medicine lab work has not shown that I have H.Pylori, but not sure how good those blood tests are.
Anyways, your thoughts and comments are appreciated.
Peyt

Some people have found that betaine affects/overstimulates the BHMT pathway. So that sounds like what may be happening.

I used to have to take betaine, but I don't need it any more. I looked back in my notes and it's hard to say what fixed it, but there is a tie-in with weak adrenals. Methylation treatment will help the adrenals.

My impression was that ACAT treatment was more for people with candida, IBS problems and so forth. Or if you had trouble with kidney stones (and possibly gall stones?)

So if your only gut problem is fat digestion, it could actually be weak adrenals and not ACAT.

So it sounds like you may be able to skip ACAT and move on to the next SNP.

If you do have weak adrenals, you may be leaking out electrolytes like crazy. I have this and have found it very helpful to replace salt, magnesium and potassium - dissolved in water and drunk four times a day.

As your adrenals get better, you'll be able to reduce the amount of electrolytes. You can use this as a gauge of progress.
 

caledonia

Senior Member
Hello again, since I put up my last post I have learned that Betaine is a methyl donor... that explains why it helped with stomach acid and fat digestion but caused agitation and anger in my case... I am Comt +/+ on both Comt genes and therefore an over-methylator with excess dopamine and norepinephrine... so now my question is, is there anyway to increase the stomach acid without having to use a methyl donor? oddly enough, I have tried lemon juice which works but causes the same side effects for me .... I guess I am stuck at step 1!

I was answering your other question when you sent this one. Looks like we came to the same conclusion on betaine. See my other answer on what to do about increasing stomach acid. (post #16 on this thread).
 

halcyon

Senior Member
Messages
2,482
If you do have weak adrenals, you may be leaking out electrolytes like crazy. I have this and have found it very helpful to replace salt, magnesium and potassium - dissolved in water and drunk four times a day.

Hi @caledonia,

What specific mechanism of electrolyte loss are you referring to here? Mineral deficiency has been a hallmark of my illness and I can't figure out why.
 

caledonia

Senior Member
Hi @caledonia,

What specific mechanism of electrolyte loss are you referring to here? Mineral deficiency has been a hallmark of my illness and I can't figure out why.

One function of the adrenals is help with electrolyte balance. If your adrenals are not working well, you will be losing electrolytes. Replacing electrolytes will help you feel better.

I also have other mineral deficiencies and supplement for those too. My doctor said something about me not being able to get my minerals via food. I'm sure some of that is due to depleted minerals in our food supply due to modern farming techniques, but there is also some illness thing going on. My gut is functioning well, so it's not that.
 

Peyt

Senior Member
Messages
678
Location
Southern California
Hi Caledonia,
Thanks so much for your reply. Now that you mention other symptoms of ACTA, I have also had kidney stones twice and if it wasn't for the 8-10 glasses of water I drink ever since my 2nd kidney stone attack I would probably continue getting them.... I was also diagnosed with something called SIBO which is a form of IBS. I have a strong feeling my ACTA +/- is activated.

Now it's very interesting you said Betaine affects BHMT,. While I don't have any +/+ on BHMT, I am +/- on BHMT / 1 and BHMT / 8..

Is there anything recommended for people with BHMT to help them be able to tolerate Betaine better? or what all is recommended? Honestly when I take HCL with my food my digestion improves so much. The usual bloat that I get 30 min after eating does not happen and my belly feels light and normal. It's just the side effects afterwards that forces me not to take it.